Abstract Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women more than men, but the biological mechanisms underlying this sexual divergence are not well understood. Convergent findings from our group and others indicate that stress contributes to the pathogenesis of AD through its effects on corticotrophin releasing factor (CRF) transmission. Recently we found that during stress, CRF coverts its function by triggering second messenger signaling through the CRF receptor 1 (CRF1) favoring Gs-PKA signaling in females, while ?- arrestin-2 signaling is favored in males. This sex bias in CRF1 signaling likely results in different phosphorylation patterns among downstream targets known to drive AD neuropathology and so provides one mechanistic explanation for the difference in AD risk by sex. Consistent with this mechanism, our preliminary data demonstrate that amyloid plaque development is much greater in female than male transgenic mice in which both human APP and forebrain-restricted CRF are overexpressed (APP+/CRF+/tTA+ mice) To continue this line of work, in this supplement, we will study the molecular and cellular mechanisms underlying sex differences in psychiatric disorders linked to AD pathogenesis and identifying the signaling pathways that may help explain why stress affects females differently. The project proposed in the diversity supplement directly ties to the funded parent grant (1 RF1 AG057884). We hypothesize that chronic stress increases the risk of AD neuropathology in female transgenic mice due to sexual dimorphism in downstream CRF1 signaling pathways and resultant AD related-protein phosphorylation, which may be reversible with specific CRF1 antagonists or PKA inhibitors. To test our hypothesis, we will confirm sex-divergent neuropathogenesis in mouse models of AD after acute and chronic stress. We will test the memory and anxiety-depressive-like behaviors and biochemical measures to determine the sex-specific vulnerability in APP/PS1 mice under chronic social isolation stress and acute restraint stress. Then we will determine the sex-specific mechanistic effects of CRF signaling impact on AD pathology. We will use viral vectors that overexpress CRF in APP/PS1 mice in a brain area-specific manner to determine how the aforementioned pathways are affected. Among the areas to be virally manipulated, the prefrontal cortex and hippocampus will be targeted to determine the sex-specific downstream effects of CRF1 signaling in vivo. Finally, we will manipulate these pathways (PKA or ?-arrestin-2) specifically. This study will demonstrate plausible mechanisms that could explain the increased risk of AD in women, and thus provide a mechanistic framework and novel targets for treatments of AD.